The overall objective of the proposed project is to investigate the potential of the gasotransmitter carbon monoxide (CO) as an anti-inflammatory agent in Sickle Cell Disease (SCD) using a novel oral formulation of CO (HBI-002). Numerous studies, both in vitro and in vivo, demonstrate that CO has cytoprotective properties through anti-oxidant, anti-inflammatory and anti-apoptotic processes. Researchers found in three studies using four different transgenic sickle cell mouse models that the heme oxygenase-1/CO pathway is key in SCD and demonstrated that very low doses of CO are a novel approach to limiting vascular stasis and down-regulating the inflammatory process. These studies provide compelling support for a potential beneficial role for CO in limiting the morbidity of SCD. Moreover, Phase 1 clinical studies of CO in both normal volunteers and SCD patients using a variety of CO delivery mechanisms have demonstrated the tolerability and safety of CO, suggesting that the very low targeted levels of COHb will not be associated with adverse outcomes. HBI-002, an oral liquid formulation, is being developed for the treatment of SCD. The oral administration of a defined dose of CO delivered by HBI-002 obviates the problems associated with previously studied inhaled or carrier-metal CO administration, enabling the potential for the necessary chronic, safe, non-toxic outpatient dosing of CO. HBI-002 comprises CO in a water-based solution of proprietary excipients to maximize CO content. Proof-of-concept manufacture of HBI-002 has been demonstrated. Pharmacokinetic and pharmacodynamic studies in rats and in two adult healthy volunteers have demonstrated proof-of-concept feasibility, tolerability, and bioavailability. The next step in development is to demonstrate that CO delivered from HBI-002 improves outcomes in an appropriate SCD animal model and to determine the minimum effective dose in SCD mice to inform dosing in planned clinical trials.